2-Thiocyanatoalkyl and aralkylcarboxamido cephalosporanic and penicillanic acid derivatives

ABSTRACT

OR, WHEN TAKEN WITH THE 3-CARBOXY   wherein R2 is -H, alkanoyloxy of 2 to 6 carbon atoms,   IN WHICH R1 is a member selected from the group consisting of -H and aryl of 6 to 10 carbon atoms; R3 is a member selected from the group consisting of -H, an alkali metal and -NH4; n is one of the integers 0, 1 and 2; Y is a member selected from the group consisting of   The antibacterial agents of this invention present the following structural formula:

United States Patent [1 1 Wei et al.

l l Z-THIOCYANATOALKYL AND ARALKYLCARBOXAMIDO CEPHALOSPORANIC AND PENICILLANIC ACID DERIVATIVES [75] Inventors: Peter H. L. Wei, Springfield; Ronald J. McCaully, Malvern, both of Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

221 Filed: Mar. 18, 1974 21 Apple N0,;4s2,0ss

[52] US. Cl .v 260/243 C; 260/239]; 424/246;

[Sl] Int. CI..,...CO7D 50l/28; CU7D 499/62; A6l K 3l/545', A6lK 31/43 [58] Field of Search 260/243 C [56] References Cited OTHER PUBLICATIONS Sassiver et al, Advances in Applied Microbiology, Vol. I], pp. l63-236, D. Perlmzm, ed. Academic Press, N.Y, (I970) pp, I63, 170, 177 relied on. Koninklijke Nederlandische Gisten Spiritusfuhriek N.\/., Chemical Abstracts, Vol. 75, 88.62% (197! Primary Exuminer-Donaltl (i. Dzlus Axsixlan! IixumincrDiunu (it Rivers Attorney, Agent, or FirmRichurd K. Jackson [57] ABSTRACT The antibacterial agents oi this invention present the following structural formula:

[ Dec. 9, 1975 SCN in which R is a member selected from the group consisting of -H and aryl of 6 to [0 carbon atoms; R is a member selected from the group consisting of H. an alkali metal and NH,,; n is one of the integers l), l and 2; Y is 11 member selected from the group consisting of or, when taken with the 3-curboxy group,

4 Claims, N0 Drawings Z-THIOCYANATOALKYL AND ARALKYLCARBOXAMIDO CEPI-IALOSPORANIC AND PENICILLANIC ACID DERIVATIVES In accordance with this invention there is provided antibacterial agents of the formula:

SCN l I i s R -(CH -CHOONH f in which R is a member selected from the group consisting of -H and aryl of 6 to 10 carbon atoms; R is a member selected from the group consisting of H, and alkali metal and NH n is one of the integers 0, 1 and 2; Y is a member selected from the group consisting of H3 CH,R= X and CH,

wherein R is I-l, alkanoyloxy of 2 to 6 carbon atoms,

N Iii '1' -s s cn f -s {N H or, when taken with the 3-carboxy group,

The compounds of this invention are prepared by reaction of potassium thiocyanate with a 2-haloalkyl or aralkylcarboxamido cephalosporanic or penicillanic acid derivative in an inert organic solvent at ambient temperature. The products, as recovered frequently contain a small amount of solvent which is readily removed, if desired, by additional vacuum stripping.

The preferred compounds are those of the formula:

l S R -CHCONH SCN 0 i y C0 in which R is a member selected from the group consisting -H and phenyl; and Y is a member selected from the group consisting of wherein R is -H or acetoxy.

The compounds of this invention are antibacterial agents of relatively broad spectrum activity in that they are effective inhibitors of both gram-positive and gramnegative bacteria. Their activity was established via the well known and scientifically recognized agar serial dilution testing technique whereby the minimum inhibitory concentration (MIC) required to achieve percent inhibition of various specific bacterial strains was determined. Thus, the compounds of this invention are useful in the fields of comparative pharmacology and in microbiology for the control and analysis of bacterial infestations. The antibacterial agents of this invention are used, in the manner and by the same means as other antibacterial cephalosporin and penicillin derivatives, for the control of bacterial infections.

The following examples illustrate the preparation of representative cephalosporin and penicillin derivatives. The activity of each product is presented for those specific bacterial strains against which the compound exemplified was active at or below 250 micrograms per milliliter. The representative nature of the bacterial strains employed to demonstrate antibacterial activity are indicative of the broader applicability of the compounds of this invention in the control of bacterial infestations other than those specifically referred to in each of the following examples. The bacteria are named followed by the specific strain and the concentration in micrograms per milliliter at which 100 percent inhibition occurred. The abbreviation for each bacterium are:

BA SU Bacillus subtilis BO BR Bordetella bronchiseptica ES CO Escherichia coli HE SP Herellea species KL IN Klebsiella pneumoniae NE CA Neisseria catarrhalis PR VU Proteus vulgaris PS AE Pseudomonas aeruginosa SA PA Salmonella paratyphi ST AU Staphylococcus aureus EXAMPLE I 7-( 2-thiocyanatoacetamido )cephalosporanic acid. KSCN (0.19 gram, 2 millimole) and 7-(2- Bromoacetamido) cephalosporanic acid (0.79 gram, 2 millimole) were dissolved in acetone and the solution was stirred at room temperature overnight. After filtration of the salts the filtrate was evaporated, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.35 gram of residual solid which was triturated with diethyl ether and collected.

Elemental Analysis for c,,,H,,N .o,s 1/2(C I-1,) O: Calcd: C, 43.13; H, 4.01; N, 10.77. Found: C, 42.75; H, 3.87; N, 10.93.

BA SU 6633 .976 B0 BR 4617 250 ES CO 9637 250 volume of pentane to afford the product as an amorphous solid.

Elemental Analysis for CHHI3N304S2 H O: Calcd: C, 4l.60; H, 4.62; N. ll.80. Found: C. 5 4l.l8; H, 4.70; N, ll.07.

7-(2-phenyl-2-thiocyanatoacetamido)cephalosporanic 5 acid.

BA SU HE SP NE (A PR VU SA PA ST AU ST AU ST AU 6633 7.8l 9955 250 8193 I 6896 250 H737 62.5 6538i L95 SMITH L95 (HP 125 What is claimed is:

I. A compound of the formula:

7 2-Bromo-Z-phenylacetamido )cephalosporanic acid (US. Pat. No. 3,338,897) (0.47 gram, l millimole) and potassium thiocyanate were stirred in acetone at room temperature over a period of hours.

BA SU KL PN SA PA ST All ST AU S'l' AU ST AU 6633 l003| 1 I737 6538? SMITH SLIM) 6-( 2-Thiocyanatoacetamido )penicillanic acid.

EXAMPLE Ill 6-(Z-Bromoacetamido)penicillanic acid potassium salt (CA 70, 68389i) (3.0 gram, 5.7 millimole) and potassium thiocyanate (0.72 gram. 5.7 millimole) were dissolved in l5 milliliters dimethylformamide and the solution stirred at room temperature for 2 hours. The undissolved salt was filtered and the filtrate was evaporated. The residue was dissolved in water and the aqueous solution was acidified with acetic acid. The acidic solution was extracted with ethyl acetate. The ethyl acetate extracts were combined and dried over anhydrous magnesium sulfate. The residual solid that was obtained after evaporation of the solvent was dissolved in diethyl ether and precipitated by addition to a large SON n -cucorm 2 (II-[ R 3 CO R 25 in which R is hydrogen or phenyl; R is hydrogen, alkanoyloxy of 2 to 6 carbon atoms or, when taken with the 3-carboxy group, N- 30 pyridinium',

and

R is hydrogen, an alkali metal or the ammonium ion. 2. A compound of claim I of the formula:

C 1 S R -CHCONH in which and R is hydrogen or phenyl R is hydrogen or acetoxy. 3. The compound of claim 1 which is 7-(2-thiocyanatoacetamido)cephalosporanic acid.

4. The compound of claim I which is 7-(2-phenyl-2- 50 thiocyanatoacetamido)cephalosporanic acid.

* ll i I 

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 of the formula:
 3. The compound of claim 1 which is 7-(2-thiocyanatoacetamido)cephalosporanic acid.
 4. The compound of claim 1 which is 7-(2-phenyl-2-thiocyanatoacetamido)cephalosporanic acid. 